An excitatory amino acid such as glutamic acid modulates various physiological processes such as long term potentiation (learning and memory), synaptic plasticity development, motion control, respiration, cardiovascular modulation, and perception in the central nervous system (CNS) of a mammal.
Presently, glutamate receptors are classified into two major groups, that is, “an ionotropic type in which the receptor has an ion channel structure”: ion channel type glutamate receptor (iGluR), and “a metabotropic type in which the receptor is coupled to a G protein”: metabotropic glutamate receptor (mGluR) (see, Non-Patent Document 1). It appears that receptors of either class mediate normal synaptic transmission in accordance with an excitatory pathway. It also appears that they are involved in modification of synaptic binding from the development stage throughout the lifetime (see, Non-Patent Document 2).
Eight subtypes of the metabotropic glutamate receptor that have been identified so far are classified into three groups (group I, II, and III) depending on pharmacological characteristics and intracellular second messengers to which they are coupled. Of these, group II receptor (mGluR2/mGluR3) binds with adenylate cyclase, and inhibit the accumulation of cyclic adenosine-1-phosphate (cAMP) stimulated by forskolin (see, Non-Patent Document 3). Thus, it is suggested that compounds that antagonize the group II metabotropic glutamate receptors are effective for the treatment or prevention of acute and chronic psychiatric disorders and neurological diseases.
It is recognized that a 2-amino-6-fluoro bicyclo [3.1.0] hexane-2,6-dicarboxylic acid derivative having a substituent group on position 3 has a strong antagonistic effect on group II metabotropic glutamate receptors. As such, it is effective for the treatment and prevention of psychiatric disorders such as schizophrenia, anxiety, and related ailments thereof, bipolar disorder, or epilepsy, and also of neurological diseases such as drug dependence, cognitive disorders, Alzheimer's disease, Huntington's disease, Parkinson's disease, dyskinesia associated with muscular rigidity, cerebral ischemia, cerebral failure, encephalopathy, or head trauma (see, Patent Documents 1 to 3 and Non-Patent Documents 4 to 6).
For example, as an antagonist of group II metabotropic glutamate receptor, 2-amino-3-alkoxy-6-fluoro bicyclo [3.1.0] hexane-2,6-dicarboxylic acid derivative represented by the following formula (A), a pharmaceutically acceptable salt thereof, or a hydrate thereof is disclosed (see, Patent Document 1). Since those compounds are useful as a therapeutic agent, it is believed that development of a synthetic process suitable for commercial production thereof, that is effective in terms of cost and also can be carried out on a safe and large scale, is in need.

(in the formula (A), RA and RB, which may be the same or different, each represents a hydroxyl group, a C1-10 alkoxy group, a phenoxy group, a naphthyloxy group, a C1-6 alkoxy group which is substituted with one or two phenyl groups, a C1-6 alkoxy C1-6 alkoxy group, a hydroxy C2-6 alkoxy group, an amino group, an amino group which is substituted with the same or different one or two C1-6 alkyl groups, an amino group which is substituted with the same or different one or two C1-6 alkoxy C1-6 alkyl groups, an amino group which is substituted with the same or different one or two hydroxy C2-6 alkyl groups, an amino group which is substituted with the same or different one or two C1-6 alkoxycarbonyl C1-6 alkyl groups, or a native or non-native amino acid residue represented by NRF—CHRG—A—CO2RH (in which RF and RG, which may be the same or different, each represents a hydrogen atom, a hydroxy C1-6 alkyl group, a hydroxycarbonyl C1-6 alkyl group, a C1-10 alkyl group, a phenyl group, a phenyl C1-6 alkyl group, a hydroxyphenyl group, a hydroxyphenyl C1-6 alkyl group, a naphthyl group, a naphthyl C1-6 alkyl group, an aromatic heterocyclic C1-6 alkyl group, a C1-6 alkoxy C1-6 alkyl group, an amino C2-6 alkyl group, a guanidino C2-6 alkyl group, a mercapto C2-6 alkyl group, a C1-6 alkylthio C1-6 alkyl group, or an aminocarbonyl C1-6 alkyl group, or RF and RG may bind to each other to represent a group capable of forming a methylene group, an ethylene group or a propylene group, or may together form a cyclic amino group; RH represents a hydrogen atom or a protecting group for carboxyl group; and A represents a single bond, a methylene group, an ethylene group or a propylene group); RC represents a C1-10 acyl group, a C1-6 alkoxy C1-6 acyl group, a hydroxy C2-10 acyl group, a C1-6 alkoxycarbonyl C1-6 acyl group, a hydroxycarbonyl C1-6 acyl group, or an amino acid residue represented by RI—NH—A—CH—RG—CO (wherein RG and A are as defined above, and RI represents a hydrogen atom or a protecting group for amino group); and RD and RE, which may be the same or different, each represents a hydrogen atom, a C1-10 alkyl group, a C2-10 alkenyl group, a phenyl group, a naphthyl group, a 5-membered heteroaromatic ring containing one or more heteroatoms, or a phenyl group substituted with 1 to 5 substituent groups selected from the group consisting of a halogen atom, a C1-10 alkyl group, a C1-10 alkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group, and a phenoxy group, or RD and RE may bind to each other to form a cyclic structure).
With respect to a lab-scale synthesis of antagonist substance of group II metabotropic glutamate receptor that is represented by the formula (A) and synthetic intermediate thereof, several studies have been made (see, Patent Documents 1 and 3 and Non-Patent Documents 4 and 6). For any process, an optically active compound represented by the following formula (IA) is used as a starting material for synthesis or as a production intermediate.

(RA in the above formula (IA) is as defined in the formula (A)).
Thus, from the viewpoint of establishing a process for industrial production of an antagonist substance of group II metabotropic glutamate receptor represented by the formula (A), which is believed to be useful as a therapeutic agent, it is important to develop a process of synthesizing an optically active compound represented by the formula (IA), that is effective in terms of cost, safety, and suitable for mass production. Non-Patent Document 7 discloses the enantiomer synthesis process of the optically active compound represented by the formula (IA). According to the synthetic process disclosed in Non-Patent Document 7, a catalytic asymmetric arylation developed by Trost, et al. is described as a process of synthesizing the optically active compound. By replacing the Trost ligand (N, N′-(1R, 2R)-cyclohexane-1,2-diylbis[2-diphenylphosphanylbenzamide]) that is used as an optically active ligand for the catalytic asymmetric arylation in Non-Patent Document 7 with its enantiomer (N, N′-(1S, 2S)-cyclohexane-1,2-diylbis[2-(diphenylphosphanyl)benzamide]), the optically active compound represented by the formula (IA) can be synthesized. Thus, it can be said that the asymmetric synthesis of the optically active compound represented by the formula (IA) is already disclosed in Non-Patent Document 7.
Further, a process of synthesizing a racemate of the compound represented by the formula (IA) is disclosed in Non-Patent Documents 8 and 9 and Patent Document 4. In Non-Patent Document 8, it is described that the optically active compound represented by the formula (IA) can be obtained by isolating racemate of the compound represented by the formula (IA) by using an HPLC column for isolating optical isomers. Further, in Non-Patent Document 10, it is disclosed that the optically active compound represented by the formula (IA) can be obtained with enantiomeric excess ratio of 38% and 54% based on a reaction which uses an asymmetric ligand. However, those synthetic processes essentially require an operation of isolating the optically active compound represented by the formula (IA) from enantiomers, and therefore it is difficult to say that they are more suitable for mass production than the asymmetric synthesis process disclosed in Non-Patent Document 7.